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Pasteurestin A   

8 October 2007 5,667 views 12 Comments

Mulzer, Kögl, Brecker and Warrass. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200703457. Article PDF Supporting Information Group Website

A second Angewandte from the Mulzer lab in but a few weeks, this synthesis shares a little with the previous post on Platensimycin. Both natural products contain tightly functionalised polycyclic systems, and both are potent antibiotics. However Pasteurestin A&B are active against bovine illness, not human, so are humbled slightly in that respect. This synthetic work consists of the first synthesis and also confirmation of assignment, so lets get into the chemistry.

The chemistry really gets going with an auxiliary controlled Reformatsky addition, using an unsaturated aldehyde. This tin-mediated process gave them an interesting result, in that the stereochemistry of the hydroxyl was (S-), not (R-) as in the aldol with this system. They presumed that this must be due to the low temperature at which they ran the reaction, so they repeated it at RT, and found that the product rearranged before they could isolate it. I’m a little confused about the numbering of the atoms in their scheme, and no stereochemistry is given for the eventual product, so perhaps someone else can enlighten me…

A few simple synthetic transformations then gave them the SM for the awesome Vollhardt [2+2+2] cycloaddition, which went in moderate yield to give them three ring formations in one reaction. Acceptable efficiency, I feel. The next step was interesting too, but for different reasons… the selectivity here is impressive, and discussing this with my lab-mate, we reckon that is must be delivery of one electron to give the allyl anion, which is then protonated to give the most stable alkene. Thoughts?

The next few transformations are far more easily understood, and complete Pasteurestin B in a synthetically pleasing manner. Hydroboration of the remaining alkene and oxidation gave the ketone shown, which was selectively deprotonated, trapped with carbon dioxide and methylated to give the methyl ester. This was then deprotonated again, selentated and the selenide eliminated to give the desired enone.

Deprotection then gave  Pasteurestin B in what was admittedly a rather linear route, but they were able to use a similar approach to get Pasteurestin A, showing the flexibility of the chemistry. Neat work.

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12 Comments

  • Andrei says:

    Ok…I used this Li/NH3 reduction on dienes, hoping to have a 1,4 but ..surprise I just reduced only one of the double bonds…I think it’s the most stable one that survives but depends a lot on the conformation. In their case we have a lot of strain release, in mine just to much strain introduced. Working at low temperature helps also the kinetic conditions.

  • jimbo says:

    Bulky acid, low temp… my guess is that it’s a kinetic phenomenon. Although it very well may also be the thermodynamic product, I think you would have to argue that the protonation step is reversible before invoking a thermodynamic equilibrium. I can’t really imagine tBuO- yoinking a proton off of any of the other possible olefinic products at -78C… then again, I’m not exactly a walking pKa table.

  • Elwoodcity says:

    What is the copper doing in the vollhardt cyclization? I’m not familiar with this reaction. Does anyone know, or is it simply “copper additives improved the yield so we added it” chemistry?

  • aa says:

    Elwood: I believe the copper is added in a second step (one-pot). First you irradiate with Co, to give a Co-complexed arene. Then add Cu (II) to oxidize the Cobalt and get it off the benzene.

  • ElwoodCity says:

    Or a cyclohexadiene, in this case. I imagine you could do it with three alkynes to give an arene, right?

  • excimer says:

    elwood: you sure can, though that cyclotrimerization is typically done with Co2(CO)8.

  • Liquidcarbon says:

    I think strain release explains the selectivity of Li/NH3 reduction, too.

    Does LAH make enolate from bromoisobutyrate? Why don’t they use conventional deprotonation?

  • PK says:

    anyone notice that these guys ripped a vollhardt synthesis off, taking his key steps to put together essentially the same molecule? see steps k-m:

    http://pubs.acs.org/cgi-bin/archive.cgi/jacsat/1991/113/i01/pdf/ja00001a067.pdf

    J. Am. Chem. Soc.; 1991; 113(1); 381-382.

    This is very disappointing.

  • Spiro says:

    Wow PK! This is huge. Not only steps k-m but a lot more.
    I wondered why this article was a VIP, but now I know : Very Important Plagiary.

  • TWYI says:

    More sterling work from the Angewandte referees then :|

  • Smitty says:

    My first thought was that maybe there were similarities because they are using what they refer to as a Vollhardt Cyclization, and they are making a highly similar molecule, but this clearly goes above and beyond. Anyone have thoughts on possible repercussions/retractions? I’ve seen addendums/corrections to add a reference an author inadvertantly (or not) failed to include, but they’d have to reference the Vollhardt paper in every sentence!

  • Roy21 says:

    And here I did play around with the coconut milk and using potatoes and peas to complement the curry. ,